Technical Field
The invention relates generally to Wnt compositions and therapeutic methods of using the same. The Wnt polypeptides of the invention and compositions thereof may be used therapeutically, for example for promoting muscle regeneration by promoting stem cell expansion and muscle hypertrophy.
Description of the Related Art
The Wnt family of genes encodes over twenty cysteine-rich, secreted Wnt glycoproteins that act by binding to Frizzled (Fzd) receptors on target cells. Frizzled receptors are a family of G protein coupled receptor proteins. Binding of different members of the Wnt-family to certain members of the Fzd family can initiate signaling by one of several distinct pathways. In the “canonical pathway,” activation of the signaling molecule, Disheveled, leads to the inactivation of glycogen synthase kinase-3 (GSK3β), a cytoplasmic serine-threonine kinase. The GSK-3β target,
β-catenin, is thereby stabilized and translocates to the nucleus where it activates TCF (T-cell-factor)-dependant transcription of specific promoters (Wodarz, 1998, Dierick, 1999). “Non-canonical” Wnt pathway activation is less well-defined, but includes a subset of interactions between Wnt and Fzd that may activate Ca2+ pathway signaling and potentially PI3K signaling, Rho pathway signaling, and planar cell polarity (PCP) pathway signaling.
Wnts are secreted glycoproteins that function as paracrine or autocrine signals active in several primitive cell types. Although Wnt proteins are secreted from cells, they are found to be hydrophobic and are believed to be post-translationally modified by addition of a lipid moiety at a conserved cysteine residue and a conserved serine residue. These lipid modifications are widely accepted to be important for the biological activity and secretion of Wnt proteins. Lipidation and the low solubility of lipidated Wnts, however, are associated with low production yields when detergents are not used during formulation and thus, present a unique challenge for clinical scale production of Wnt. Thus, while Wnts have a tremendous potential for use as therapeutics in a variety of clinical settings, the therapeutic potential of Wnts has yet to be fully realized due to Wnt insolubility and corresponding insufficient production as a purified, biologically active therapeutic.
Accordingly, the art is in need of soluble, Wnt polypeptides that retain Wnt biological activity, methods for generating the Wnts on a clinical scale, and methods of using the Wnts to promote tissue formation, regeneration, maintenance and repair.